Camptothecin (CPT) is a potent inhibitor of cell proliferation, and camptothecin derivatives, such as irinotecan and topotecan, have proven valuable in treatment of solid tumors. The goal of this project to develop a clearer mechanistic and molecular understanding of repair of CPT-induced DNA damage, and to apply this knowledge to developing a rapid assay for CPT-sensitivity based on repair capability. We propose three specific aims to that end. (1) We will determine the molecular mechanism by which MRE11 contributes to repair of CPT-induced DNA damage. (2) We will elucidate the roles of RecQ family helicases and G4 DNA in CPT sensitivity. (3) We will test the utility of y-sH2AX as a biomarker for chemotherapeutic sensitivity and DNA repair. The results of the proposed research will provide an important step toward improved treatment of cancer based on stratification of tumor response to CPT.